Accumulating clinical and experimental evidence has supported an important role of the vitamin D endocrine system in the regulation of cardiovascular functions. For instance, vitamin D therapy has been shown to significantly reduce the risk of cardiovascular death among hemodialysis patients. The renin-angiotensin system (RAS) plays a central role in the maintenance of electrolyte, extracellular volume and blood pressure homeostasis;over-activation of the RAS has been well known to cause cardiovascular problems such as hypertension, cardiac hypertrophy and atherosclerosis. In the past years we had obtained a great deal of evidence demonstrating that vitamin D regulates the RAS by suppressing renin biosynthesis. We found that disruption of the vitamin D signaling in mice results in activation of the RAS, leading to high blood pressure and cardiac hypertrophy, and that 1,25-dihydroxyvitamin D3 directly suppresses renin gene transcription by a VDR-dependent mechanism. In this application, we will continue to explore the physiological and pharmacological effects of vitamin D on the RAS by proposing three Specific Aims. The first Aim is to further define the role of vitamin D and parathyroid hormone (PTH) in the regulation of the RAS in vivo by transgenic approach. We will study transgenic (Tg) mice overexpressing human (h) VDR in renin-producing JG cells as well as VDR knockout (KO) mice that express the hVDR transgene (VDRKO-hVDR) only in JG cells. Parallel analyses of wild-type, VDRKO, Tg-hVDR and VDRKO-hVDR mice will allow us to further clarify the in vivo role of vitamin D and PTH in the regulation of renin gene expression. The second Aim is to elucidate the molecular mechanism underlying the regulation of renin gene expression by vitamin D. Based on our existing evidence, we will focus on exploring two indirect mechanisms: one is that vitamin D suppresses renin expression via stimulating other transcriptional represser, and the other is that VDR physically interacts with other factors that regulate renin transcription via cyclic AMP response element (CRE) in renin gene promoter. The third Aim is to explore the potential of vitamin D analogs as renin inhibitors and anti- hypertensive agents. Our discovery of vitamin D as a potent negative endocrine regulator of the RAS provides a molecular basis to explore the potential of vitamin D analogs as renin inhibitors for therapeutic purposes. We have identified a group of low calcemic vitamin D analogs that can effectively suppress renin biosynthesis and plasma renin activity in cell cultures and in mice. We will further test the efficacy of these analogs to reduce renin production and to lower blood pressure in high-renin hypertensive animal models such as the Goldblatt hypertensive rats and spontaneously hypertensive rats. These studies will further enhance our understanding of the novel physiology of the vitamin D endocrine system and its pharmacological applications in the regulation of the RAS and cardiovascular system.